Poly-4-hydroxybutyrate (P4HB) and copolymers thereof can be produced using transgenic fermentation methods, see, for example, U.S. Pat. No. 6,548,569 to Williams et al., and are produced commercially, for example, by Tepha, Inc. (Lexington, Mass.). Poly-4-hydroxybutyrate (P4HB, TephaFLEX® biomaterial) is a strong, pliable thermoplastic polyester that, despite its biosynthetic route, has a relatively simple structure.

The polymer belongs to a larger class of materials called polyhydroxyalkanoates (PHAs) that are produced by numerous microorganisms (see, for example, Steinbüchel A., et al. Diversity of Bacterial Polyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128:219-228 (1995)). In nature these polyesters are produced as storage granules inside cells, and serve to regulate energy metabolism. They are also of commercial interest because of their thermoplastic properties, and relative ease of production. Several biosynthetic routes are currently known to produce P4HB:

This schematic shows some of the known biosynthetic pathways for the production of P4HB. Pathway enzymes are: 1. Succinic semialdehyde dehydrogenase, 2. 4-hydroxybutyrate dehydrogenase, 3. diol oxidoreductase, 4. aldehyde dehydrogenase, 5. Coenzyme A transferase and 6. PHA synthetase.
Chemical synthesis of P4HB has been attempted, but it has been impossible to produce the polymer with a sufficiently high molecular weight that is necessary for most applications (see Hori, Y., et al., Polymer 36:4703-4705 (1995) and Houk, et al., J. Org. Chem., 73(7):2674-2678 (2008).
U.S. Pat. Nos. 6,245,537, 6,623,748 and 7,244,442 describe methods of making PHAs with little to no endotoxin, which is suitable for medical applications. U.S. Pat. Nos. 6,548,569, 6,838,493, 6,867,247, 7,268,205, and 7,179,883 describe use of PHAs to make medical devices. Copolymers of P4HB include 4-hydroxybutyrate copolymerized with 3-hydroxybutyrate or glycolic acid (U.S. patent application No. 2003/0211131 by Martin and Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No. 6,323,010 to Skraly, et al.). Methods to control molecular weight of PHA polymers have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.
PHAs with controlled degradation and degradation in vivo of less than one year are disclosed by U.S. Pat. Nos. 6,548,569, 6,610,764, 6,828,357, 6,867,248, and 6,878,758 to Williams, et al. and WO 99/32536 to Martin, et al. Applications of P4HB have been reviewed in Williams, et al., Polyesters, III, 4:91-127 (2002), and by Martin, et al. “Medical Applications of Poly-4-hydroxybutyrate: A Strong Flexible Absorbable Biomaterial”, Biochem. Eng. J. 16:97-105 (2003). Medical devices and applications of P4HB have also been disclosed by WO 00/56376 to Williams, et al. Several patents including U.S. Pat. Nos. 6,555,123, 6,585,994, and 7,025,980 describe the use of PHAs in tissue repair and engineering.
In the practice of surgery there currently exists a need for absorbable non-wovens with improved performance. These non-wovens can be used, for example, for soft tissue repair, to reinforce tissue structures, to separate tissues, and to serve as tissue engineering scaffolds, including guided tissue regeneration scaffolds. They may also be used as components of other devices. A number of other absorbable materials have been used to produce non-wovens for use in surgery. For example, non-wovens have been made from polyglycolic acid (PGA) or copolymers containing lactic acid. These materials do not, however, have ideal properties for many procedures and applications. Non-wovens made from polyglycolic acid breakdown too rapidly for many applications, and release acidic degradation products that can cause inflammatory reactions.
WO 04/101002 to Martin et al. discloses monofilament and multifilament knitted meshes of P4HB, produced by knitting monofilament and multifilament fibers of P4HB. WO 09/085,823 to Ho, et al. discloses medical devices containing melt-blown non-wovens of poly-4-hydroxybutyrate and copolymers thereof. Notably, the process of melt blowing can limit the utility of this method to produce non-wovens, particularly when it is necessary to produce three-dimensional non-woven fabrics and devices, and apply coatings of non-wovens on scaffolds or other materials. The process of melt extrusion causes a dramatic loss in the molecular weight of the polymer such that the molecular weight of the polymer in the melt blown non-woven is substantially less than in the polymer feed. The lower molecular weight of melt blown non-woven is a particular disadvantage when it is desirable to retain mass and/or mechanical properties, such as burst strength, in vivo, for a prolonged period of time, since lower molecular weight P4HB non-wovens degrade faster in vivo than higher molecular weight P4HB non-wovens.
WO 95/23249 to Noda, et al. discloses non-woven fabrics prepared from other polyhydroxyalkanoates, namely, poly-3-hydroxybutyrate (PHB) and poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV), by dry spinning for use in non-medical applications such as disposable absorbent articles, including diapers, incontinence articles, and sanitary napkins. These materials, however, have substantially different thermal and physical properties than poly-4-hydroxybutyrate and copolymers thereof. For example, P3HB has a melting point and glass transition temperature of approx. 180° C. and 1° C., respectively, and an elongation to break of about 3%, whereas P4HB has a melting point of 60° C., a glass transition temperature of approx. −51° C., and elongation to break of around 1,000%. As such, P3HB is a brittle polymer that has properties resembling polystyrene whereas P4HB is a strong but extensible polymer similar to low density polypropylene. Furthermore, P3HB and PHBV have also been reported to degrade very slowly in vivo, with material still present after 24 months (Duvernoy, et al. Thorac. Cardiovacs. Surgeon, 43:271-274 (1995)), and are therefore not well suited for many in vivo surgical applications.
It is an object of the present invention to provide methods to produce dry spun non-wovens of absorbable P4HB and copolymers thereof that have relatively high burst strengths, and without substantial loss of the polymer molecular weight during processing.
It is a further object of the present invention to provide continuous processes to produce medical devices comprising non-wovens by dry spinning, including processes to form medical devices by coating other materials and scaffolds with dry spun non-wovens, and processes to dry spin P4HB and copolymers thereof into non-wovens without substantial loss of molecular weight during the spinning process.
It is another object of the present invention to provide dry spun non-wovens which are biocompatible and can be used in medical applications, for example, as implants such as devices for soft tissue repair, replacement, and regeneration, temporary tissue support, tissue separation, as well as devices or components of devices for tissue in-growth (or guided tissue regeneration) and tissue engineering.
It is therefore an object of the invention to provide continuous processes for dry spun non-woven production, which can be incorporated into or formed into medical devices with excellent physical and mechanical properties for medical applications.